The Collaborative AIDS Program of Research in South Africa (CAPRISA) is a multi-institutional team with well established local leadership and expertise in the areas of basic and molecular epidemiology, virology, immunology, infectious disease medicine, HIV primary care and service delivery, bioinformatics, social and behavioral science, statistics, ethics and health policy. CAPRISA has three goals; i) to undertake globally relevant and locally responsive research that contributes to understanding HIV pathogenesis and epidemiology as well as the nexus between tuberculosis and AIDS care, ii) to build local research infrastructure though cores of expertise and iii) to provide training through research fellowships tenable both in South Africa and the USA. CAPRISA comprises four research projects. (1) The epidemiological studies on monitoring and deciphering the nuances of the evolving HIV/AIDS epidemic in a rural South African community lay the foundation for assessing the impact of therapeutic and prevention programs at community level. (2) The clinical, immunological and virological studies on acute HIV infection elucidate the host and viral factors influencing the viral set point and immune escape. Since the set point is currently the best prognostic marker of progression to AIDS, these data could have a substantial impact on future therapeutic and prevention research. (3) Linked to this is the study on highly exposed persistently seronegative individuals, which will provide clues to the genetic and immunological mechanisms of protection from HIV infection. (4) The innovative clinical study integrating antiretroviral therapy into the tuberculosis directly observed therapy strategy could provide a mechanism for facilitating the implementation of antiretroviral therapy, with high levels of adherence, in developing countries. An Executive Committee comprising the Project and Core Leaders governs CAPRISA. Besides managing the day-to-day CAPRISA operations, this committee also develops plans for future studies for review by the CAPRISA Scientific Advisory Board. Local research infrastructure is built through Cores for administration, epidemiology/biostatistics, viral diversity/bioinformatics and immunology. South African laboratories will be equipped to conduct assays locally and international collaborators will assist with training, advice, support, assay development and quality control. The training program includes several long- and short-term fellowships each year in laboratory science, clinical and epidemiological research and ethics. If successful, CAPRISA could make seminal contributions to understanding the epidemiology of the subtype C, heterosexually acquired HIV infection, elaborating early immune responses in HIV infection, developing an understanding of the phenomenon of resistance to HIV infection, and making a contribution to AIDS care relevant to the developing world.